Biology subjects

Ziari, N.

Publications and source records attributed to Ziari, N..

4 recordsLinked to original sources

bioRxiv2025

Nutrient-Sensing Nuclear Receptor PPARα Controls Liver Proteostasis

Peroxisome proliferator-activated receptor alpha (PPAR) is a nuclear receptor that orchestrates metabolic adaptation to fasting by regulating hepatic lipid and glucose metabolism. While these functions are well established, its role in protein homeostasis, another energy-intensive process, has remained unclear. Here, we performed multi-omics analyses in wild-type and PPAR knockout mice treated with the PPAR agonist fenofibrate to define its broader role in proteostasis. Interestingly, chronic PPAR activation suppressed hepatic secretory pathways, reducing secretome gene expression and circulating serum proteins, and downregulated genes involved in endoplasmic reticulum (ER) translocation, glycosylation, folding, and trafficking. Concurrently, PPAR activation enhanced proteasome activity, which was associated with selective induction of proteasome 26S subunit non-ATPase (PSMD) family members. In addition, hepatic protein synthesis was strongly attenuated. This was associated with an increase in the inhibitory phosphorylation of the eukaryotic translation initiation factor 2 (eIF2), that in turn was linked to disrupted iron homeostasis. Together, these findings identify PPAR as a regulator of proteostasis, suppressing protein synthesis and secretion while promoting protein degradation pathways. Beyond its canonical role in lipid and glucose metabolism, we conclude that PPAR exerts an additional energy-conserving function by coordinating proteostasis, expanding our understanding of its systemic metabolic role.

physiology↗

bioRxiv2022

Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy

Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951 with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor properties of both chemotypes, were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex containing the protein TRIM28/KAP1, an allosteric modulator known to regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds provide starting points for development of next-generation non-toxic, pan-cancer therapeutics.

cancer biology↗

bioRxiv2021

Aging alters the metabolic flux signature of the ER unfolded protein response in vivo in mice

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRER less effective in resolving proteotoxic stress.

physiology↗

bioRxiv2020

Metabolic flux signatures of the ER unfolded protein response in vivo reveal decreased hepatic de novo lipogenesis and mobilization of lipids from adipose tissue to liver

The unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases, including non-alcoholic fatty liver disease. Here, we characterize the UPRER induced metabolic changes in mouse liver through in vivo metabolic labeling and mass spectrometric analysis of proteome and lipid fluxes. We induced ER stress in vivo via tunicamycin treatment and measured rates of proteome-wide protein synthesis, de novo lipogenesis and cholesterol synthesis serially over a three-day period, thereby generating a metabolic "signature" of the UPRER over time. Synthesis of most proteins was suppressed under ER stress conditions, including proteins involved in lipogenesis, consistent with reduced de novo lipogenesis at 48 and 72 hours. Electron microscopy revealed striking morphological changes to ER and H&E staining showed lipid droplet enriched livers under ER stress. Pre-labeling of adipose tissue prior to ER stress induction revealed mobilization of lipids from adipose to the liver. Interestingly, the source of these lipids was uptake of free fatty acids, not whole triglycerides or phospholipids from lipoproteins, as demonstrated by replacement of the triglyceride-glycerol moiety in liver concurrently with increased incorporation of labeled palmitate from adipose. We also induced ER stress by a high-fat diet and observed similar metabolic flux signatures, suggesting that this mechanism may play a role in the progression of fatty liver disease. This flux-based approach provides a powerful tool to identify novel regulators of ER stress and potential targets for pharmacological intervention.

physiology↗